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140

Section 3

Organic syndromes of schizophrenia:

10PsychotomimeticeffectsofPCP,LSD,

and Ecstasy: pharmacological models

of schizophrenia?

Vibeke S. Catts and Stanley V. Catts

Facts box

neuronal dysfunction, to PCP-induced

r
Phencyclidine (PCP), ketamine, D-lysergic
psychotomimetic effects in healthy

acid diethylamide (LSD) and

volunteers and patients with schizophrenia.

3,4-methylenedioxy-methamphetamine

r
Ketamine is considered to be a safe and valid
(MDMA) have been variously referred to as

model of PCP psychosis and applicable to

schizophrenomimetics, psychotogens, or

preclinical human studies.

psychotomimetics.

r
More translational science is needed to

r
There have been many reports that these

relate animal findings to humans and vice

drugs can induce psychotic symptoms

versa.

(hallucinations, delusions, formal thought

disorder, or catatonia-like abnormalities) in
In this chapter, the potential role of glutamatergic and
the absence of delirium.

r

serotonergic neurotransmitter systems in the patho-There is abundant evidence that PCP induces
physiology of schizophrenia is examined from the
psychotic disorder beyond the acute

perspective of the psychotomimetic effects of i) phen-symptoms of intoxication.

cyclidine (PCP) and ketamine, noncompetitive antag-r
There is no clear evidence that either LSD or
onists of the N-methyl-D-aspartate (NMDA) gluta-MDMA induces psychotic disorder, let alone
matergic receptor that bind at the intrachannel site of
schizophrenia, in individuals who did not

the receptor to prevent calcium ion flux into the cell; ii)
have vulnerability to schizophrenia

D-lysergic acid diethylamide (LSD), a serotonin-like
premorbidly.

hallucinogenic indoleamine that acts as an agonist at
r
PCP and ketamine are noncompetitive

the serotonin-subtype-2A (5HT2A) receptor; and iii)
antagonists of the N-methyl-D-aspartate

3,4-methylenedioxy-methamphetamine (MDMA), an
(NMDA) glutamatergic receptor that bind at

indirect serotonin agonist. These drugs, variously
the intrachannel site of the receptor to

called hallucinogens, schizophrenomimetics, psy-prevent calcium ion flux into the cell.

chotogens, or psychotomimetics, have shown in com-r
LSD is a serotonin-like hallucinogenic
mon reports that they can induce psychotic symptoms
indoleamine that acts as an agonist at the

(hallucinations, delusions, formal thought disorder, or
serotonin-subtype-2A (5HT2A) receptor,

catatonia-like abnormalities) in the absence of delir-

and MDMA is an indirect serotonin

ium. The primary question addressed herein, whether
agonist.

PCP-induced psychosis is a valid model of schizophrer
nia, gives rise to additional questions about the
Rodent and primate models induced by PCP

validity of ketamine challenge at subanesthetic doses
and analogues have been presented as

in humans as a model of PCP psychosis, and in turn,
models of human schizophrenia, with

questions about the validity of drug-induced changes
construct validity, showing homologous

in nonhuman animals (rodents, monkeys) treated
behavior, cognitive deficits, alterations in
with PCP and its analogues (ketamine or dizocilpine
regional brain activation, and underlying

[MK-801]) as models of PCP-induced psychosis.

Organic Syndromes of Schizophrenia – Section 3

unsuccessful: diazepam
[7]
appeared to be as effective as haloperidol
[8].
Phencyclidine was withdrawn
For each drug of interest, this chapter reviews the evi-from the market for human use in 1965. A veterinar-dence for psychotomimetic effects in humans, in terms
ian formulation was introduced in 1967 but because of
of induced transient symptoms with acute dosing, and
a growing abuse problem, all legal manufacture of the
the epidemiological association between formal psy-drug was ceased in 1979.

chotic disorder and chronic abuse. The phenomeno-Despite its propensity to cause adverse reactions,
logical similarity of drug-induced symptoms and the
PCP abuse became widespread. It was relatively inex-clinical features of schizophrenia are closely examined.

pensive to manufacture and the starting materials,
Wherever available, human neuroimaging and clini-used in many industrial processes, were readily avail-cal biomarker studies are considered for comparison of
able
[9].
Illicit PCP use first appeared in 1965 on the
drug-induced effects and deficits seen in schizophre-West Coast of the United States
[10].
Initially the drug
nia. Ketamine is included in the review because most
was ingested orally (called the “PeaCe Pill”). Slow oral
experimental evidence supporting the validity of the
absorption resulted in inadvertent high dosing and fre-PCP model arose from studies using ketamine in
quent adverse reactions, limiting its appeal
[9].
Once
humans. The literature on LSD and MDMA is briefly
street users discovered that the dose could be lowered
reviewed for comparative purposes.

and self-titrated by smoking PCP added to cigarettes,
illicit use escalated. National surveys in the United
Phencyclidine

States indicate that peak use of PCP occurred between
Phencyclidine [1-(1-phenylcyclohexyl)piperidine hy-1977 and 1979
[11, 12].
Between 1976 and 1977 the
drochloride] was synthesized in 1956
[1].
Preclinical
National Institute of Drug Abuse (NIDA) reported a
testing indicated that PCP might be a safe intravenous
doubling (from 3%–5.8%) of the number of 12-to
(IV) anesthetic because it induced analgesia and anes-17-year-old users of PCP, and a 50% increase (from
thesia without circulatory or respiratory depression
9.5%–13.9%) in 18-to 25-year-old users
[9].
A sur-

[1].
The term “dissociative anaesthetic” was coined
vey of 319 adult users reported negative events on
because PCP induced a state of detachment and disso-100% of use occasions
[13],
including speech diffi-ciation from painful and environmental stimuli, with-culties (80%), perceptual disturbances (75%), restless-out causing unconsciousness. During anesthesia the
ness (76%), disorientation (63%), anxiety (61%), para-patient remained immobile with fixed sightless star-noia (34%), hyperxcitability (27%), irritability (22%)
ing, absent facial expression, and open mouth
[2].
PCP

and mental confusion (22%). The extent to which PCP

is a highly lipid soluble and readily crosses the blood-posed serious problems at that time was indicated by
brain barrier, inducing CNS effects within minutes of
the US. Drug Abuse Warning Network (DAWN), a
IV injection. The serum half-life of PCP was reported
national reporting system for drug-related deaths and
to vary between 4 to 72 hours
[3].

hospital emergencies. Data from the 662 participating
Early clinical use revealed that many patients expe-emergency centers showed 111 events in October 1976

rienced psychotic symptoms as they emerged from
versus 54 events in October 1974; and reports of PCP-PCP anesthesia
[2, 4, 5, 6].
Emergence phenomena
related deaths increased over roughly the same period
included agitation, bizarre behavior, paranoia, formal
from 17 in April 1976 to 30 in March 1977
[9].
Unde-thought disorder, hallucinations, and delusions, typ-sirable psychological reactions were frequent.

ically lasting for 12–72 hours but occasionally per-Although a strong relationship between PCP abuse
sisting for up to 10 days
[4, 6]
. Symptoms were
and psychotic disorder was evident, the face validity
schizophrenia-like, especially the motor changes
[5].

of PCP-induced psychosis as a model for schizophre-Flat facies, fixed staring, manneristic grimacing, gen-nia also requires close phenomenological similarity
eralized rigidity, and plastic stiffness very similar to
between the two disorders. To make this compari-

“cerea flexibilitas” occurred. Stereotypic verbalizations
son, three types of PCP-related conditions need to
of select phrases were uttered. PCP-induced agitation
be distinguished: acute intoxication without delirium
was associated with atypical movements: head rolling
(a ‘“bad trip”), acute intoxication with delirium; and
or shaking the head from side to side was common.

the more persistent drug-induced psychotic disor-Attempts to prevent emergence reactions by pretreat-der
[14]
. Duration of acute PCP intoxication paral-

ment with haloperidol or diazepam were relatively
lels the half-life of the drug. Symptom severity is dose
Chapter 10 – Psychotomimetic effects of PCP, LSD, and Ecstasy

dependent. Acute intoxication without delirium lasts
ing a family history or personal history of schizophre-about 3–8 hours and presents with restlessness,
nia and an absence of previous psychiatric history or
agitation, hallucinations, delusions, nystagmus, hyper-evidence of prodromal psychosocial deterioration
[9,

tension, tachycardia, ataxia, slurred speech, and hyper-

14, 21, 22]
. Although most cases of PCP-psychosis
reflexia
[14, 15, 16].
PCP-induced delirium repre-resolved within 2 weeks without sequel
[22],
about
sents a more profound degree of toxicity, which
25% of patients went on to have a typical history of
can persist for a week. Dose-dependent clinical fea-schizophrenia
[27]
. This subgroup of patients took
tures include clouding of consciousness, disorien-months rather than weeks to recover from the first
tation, toxic psychosis, vomiting, hypersalivation,
PCP-related psychotic episode, tended to have a fam-spasticity, EEG slowing or seizures, and respiratory
ily history of schizophrenia and a personal history of
depression
[14, 15, 17, 18, 19].